EP0520237A2 - Bone replacement material containing fibroblast growth factors - Google Patents
Bone replacement material containing fibroblast growth factors Download PDFInfo
- Publication number
- EP0520237A2 EP0520237A2 EP92109712A EP92109712A EP0520237A2 EP 0520237 A2 EP0520237 A2 EP 0520237A2 EP 92109712 A EP92109712 A EP 92109712A EP 92109712 A EP92109712 A EP 92109712A EP 0520237 A2 EP0520237 A2 EP 0520237A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- material according
- bone
- bone replacement
- replacement material
- porous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000316 bone substitute Substances 0.000 title claims abstract description 53
- 102000018233 Fibroblast Growth Factor Human genes 0.000 title claims abstract description 37
- 108050007372 Fibroblast Growth Factor Proteins 0.000 title claims abstract description 37
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 62
- 239000011159 matrix material Substances 0.000 claims abstract description 34
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 16
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 13
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- 239000007943 implant Substances 0.000 claims description 54
- 239000000463 material Substances 0.000 claims description 52
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- 239000011707 mineral Substances 0.000 claims description 21
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 13
- 238000002513 implantation Methods 0.000 claims description 11
- 239000001506 calcium phosphate Substances 0.000 claims description 8
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 8
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- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 claims description 3
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- 150000001875 compounds Chemical class 0.000 claims 1
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 claims 1
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- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
- A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/3094—Designing or manufacturing processes
- A61F2002/30968—Sintering
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the invention relates to bone substitute materials which contain one or more polypeptides with the biological effect of fibroblast growth factors in a porous matrix.
- Bone replacement materials are understood to mean materials that serve as implants for the replacement or reconstitution of bone structures due to defects after a surgical or illness-related surgical intervention.
- implant shaped bodies such as various types of bone prostheses, bone connecting elements, for example in the form of medullary cavity nails, bone screws and osteosynthesis plates, implant materials for filling cancellous bone defects or tooth extraction cavities, and for plastic-surgical treatment of contour defects in the jaw facial area.
- implant materials are regarded as particularly favorable if they have a high bioactivity, namely in that they are accepted in the organism and be integrated into it.
- Bone replacement implant materials made of synthetic or non-body related materials can, depending on their nature and nature, show bioinert to bioactive behavior. However, the healing results of the body's own bone grafts have not yet been achieved by any synthetic implant material.
- the invention was therefore based on the problem of providing a bone replacement material whose biological activity comes as close as possible to that of the body's own bone grafts.
- the invention therefore relates to a bone substitute material which contains one or more polypeptides with the biological effect of fibroblast growth factors in a porous matrix.
- the invention particularly relates to such a bone substitute material in which the porous matrix is a mineral matrix, preferably based on calcium minerals.
- Fibroblast growth factors which belong to the class of the body's own peptide growth factors, were originally detected as substances in the brain and pituitary gland and isolated therefrom and showed a growth-promoting activity of fibroblasts.
- FGFs are known to be effective vascularizing factors that are responsible for, among other things, neovascularization in wound healing. Further details on FGFs including their modification products, their isolation or manufacture, their structure, Their biological activities and their mechanisms as well as corresponding medical applications can be found in the now extensive specialist literature. A comprehensive overview is provided, for example, by A. Baird and P. Böhlen, Fibroblast Growth Factors, in: Peptide Growth Factors and their Receptors I (editors: MB Sporn and AB Roberts) Springer Verlag Berlin, Heidelberg, New York 1990.
- DBM demineralized bone matrix
- DBM is practically unsuitable as an implant material for bone replacement due to the lack of mechanical strength. From the published findings it was in no way deduced that with the bone replacement material according to the invention a material could be provided that combines the mechanical properties of artificial implant materials with the biological activity that only bone grafts have.
- the bone substitute materials according to the invention are characterized by the common feature that they contain one or more polypeptides with the biological effect of FGF in a porous matrix.
- Suitable growth factors according to the invention are therefore not only the "classic" FGFs such as the acidic fibroblast growth factor (aFGF) and the basic fibroblast growth factor (basic Fibroblast Growth Factor, bFGF), but also all peptide growth factors which show biological effects of FGF.
- the narrow circle of FGFs includes native FGFs, in particular bovine and human origin, and recombinantly produced FGFs.
- Recombinant human aFGF and bFGF are particularly preferred. More information on recombinantly produced bovines such as human aFGFs and bFGFs can be found, for example, in the following patent documents: EP 228 449, EP 248 819, EP 259 953, EP 275 204.
- Muteins which are different from aFGF or bFGF also include a further group of FGFs differ to a certain extent in the number and / or sequence of the amino acids without this being associated with a significant change in activity.
- the further circle of FGFs finally also includes related peptides with, in some cases, clearly different amino acid sequences with the effect of FGF as well as activity that enhances the effect of FGF.
- the following patent documents may be cited as references: EP 148 922, EP 226 181, EP 281 822, EP 288 307, EP 319 052, EP 326 907 and WO 89-12645.
- FGFs in the sense of the invention also include derivatives of these peptides, which are obtained with stabilizing and / or activity-increasing agents.
- stabilizing and / or activity-increasing agents are, in particular, acid-stabilized forms of aFGF and bFGF which contain, for example, glycosaminoglycans such as heparin, heparin fragments, heparan sulfate and dermatan sulfate or glucan sulfates such as dextran sulfate and cyclodextrin sulfate as stabilizing agents.
- FGF derivatives of this type are described, for example, in EP 251 806, EP 267 015, EP 312 208, EP 345 660, EP 406 856, EP 408 146, WO 89-12464, WO 90-01941 and WO 90-03797.
- Forms of recombinantly produced human bFGF as described in EP 248819 are particularly preferred for use in the bone replacement materials according to the invention.
- the FGFs can be present in a concentration of 1 ng / cm3 - 1 mg / cm3.
- concentration within the range mentioned may depend on the type and shape and the activity of the FGF to be used in the individual case, and on the nature of the implant material provided in the individual case and its inherent bioactivity.
- concentration of FGF is preferably in the range between 1 ⁇ g / cm3 to 100 ⁇ g / cm3.
- Implant materials can be divided into the classes mineral, in particular ceramic materials, physiologically acceptable metallic materials, physiologically acceptable polymer materials and composite materials made of two or more materials of the type mentioned. These materials as a whole can form a porous matrix, for example in the form of porous implant shaped bodies, or only certain portions of the material can be present as porous material or certain areas of an implant shaped body can represent a porous matrix.
- the last two cases can be implemented, for example, in such a way that a composite material or a bone cement contains a porous component or an implant is provided with a porous surface coating or a correspondingly roughened surface.
- materials that are mineral and in particular ceramic in nature are preferred from the material side.
- bio-inert materials such as oxide ceramic materials, can be biologically activated by loading with FGF and thus show significantly better waxing and healing behavior.
- preferred mineral materials are those that are bioactive per se. This applies primarily to materials based on calcium-containing materials, such as calcium carbonate, calcium phosphates and von systems derived from these connections. From the group of calcium phosphates, preferred are hydroxyapatite, tricalcium phosphate and tetracalcium phosphate.
- mineral-based implant materials usually only guarantee high mechanical stability if they are used as ceramics, i.e. thus in the form of materials or workpieces sintered at sufficiently high temperatures.
- Bone replacement material based on calcium phosphate ceramics is considered bioactive due to its chemical relationship with the mineral phase of natural bones.
- natural bone In its mineral phase, natural bone consists predominantly of hydroxyapatite, a calcium phosphate of the empirical formula Ca5 (PO4) 3OH.
- Hydroxyapatite of synthetic or organic origin for example from natural bone material, is therefore a frequently used raw material for the production of implants for bone replacement.
- Hydroxyapatite ceramic is essentially non-absorbable in the organism. This means that the foreign material remains practically unchanged over a long period of time and the integration into the organism takes place essentially through overgrowth with existing and newly formed bone and ingrowth in the surrounding tissue.
- Tricalcium phosphate is absorbable in the organism under certain circumstances. Tetracalcium phosphate is essentially non-bioabsorbable.
- Porous calcium phosphate ceramics show particularly favorable ingrowth behavior.
- Materials based on natural bone which are mineralized by various treatments and converted into a ceramic system, are particularly preferred, the structure of the bone being retained as far as possible.
- Common to the processes is the removal of the organic bone components and the subsequent solidification to the ceramic by sintering at appropriate temperatures.
- the organic components are removed by chemical solution processes or by pyrolytic processes.
- Bone ceramic implants show considerable biological advantages in waxing behavior and healing in the organism due to their excellent agreement with the pore system of natural bone.
- Cancellous bone ceramic is particularly preferred due to its highly porous, three-dimensional open-pored network structure.
- Shaped bodies made of ceramic material are primarily used for the replacement of load-bearing bone structures that have to withstand high mechanical loads.
- bone prostheses and bone connection elements such as intramedullary nails, bone screws and osteosynthesis plates.
- the bone substitute materials according to the invention are loaded with FGF after the implantation in the contact area and, depending on whether they are permeable due to porosity and / or absorption, also inside stimulate a significant new formation of mineral bone matrix. In any case, this is significantly higher than in corresponding unloaded implants.
- a pronounced synergistic effect could be observed with porous implants based on calcium minerals, in particular calcium phosphate ceramics, loaded with FGF.
- Preclinical model experiments with bone ceramic implants loaded with FGF showed complete incorporation into the bones six weeks after the implantation through ingrowth and infiltration with newly formed, predominantly mineralized bone matrix.
- the positive influence of FGF on the healing behavior of implants for bone replacement can be transferred to practically all types of bone replacement materials and implant materials, provided that they are of such a design that they form a porous matrix for the absorption of FGF and re-release have the organism, expediently at least primarily in the area of contact with the body tissue.
- implants made of metallic materials that are porous in themselves or have a porous surface coating, preferably made of bioactive hydroxyapatite, or that have a porous structured or at least roughened surface also meet these requirements.
- the bone replacement materials according to the invention can be present not only as shaped implants, but also in powder or granule form, depending on the location and the purpose of use.
- Composite materials are preferably those in which at least one component is present as a porous matrix for receiving FGF.
- Appropriate bone replacement materials based on composite materials are expedient, in which a porous mineral matrix is in powder or granule form and forms a shaped body in combination with a physiologically acceptable polymer material.
- Composite materials of this type can be found in the relevant technical literature, for example in patent documents WO 90-01342 and WO 90-01955, in which implant materials based on calcium phosphate or bone ceramic particles and bioresorbable polymer are described.
- Bone cements mainly consist of acrylate systems that contain mineral fillers, mostly based on calcium compounds.
- mineral fillers mostly based on calcium compounds.
- porous hydroxylapatite powder or granulate loaded with FGF can be used as filler component in bone cement.
- the production of the bone replacement materials according to the invention by loading the respective porous matrix with polypeptides with the effect of FGF is per se problem-free. It is expedient to start from a suitable liquid or semi-liquid preparation of FGF, for example in the form of a buffered aqueous solution, a suspension or a gel, and allow it to be completely absorbed into the porous matrix of the bone substitute material in the intended dosage amount. With this, or after a possibly necessary Drying, the bone replacement material can already be used or can be stored according to the precautionary measures required for such materials for medical use. In this way, porous shaped implants, preferably made of bone ceramic, implants provided with a porous surface and porous particulate components for composite materials and bone cements can be loaded with FGF.
- the bone replacement material according to the invention is in the form of a ready-to-use implantation set consisting of two or more separate components, in which one component contains the porous matrix and another component contains a solution of the polypeptide with the effect of FGF.
- a ready-to-use implantation set consisting of two or more separate components, in which one component contains the porous matrix and another component contains a solution of the polypeptide with the effect of FGF.
- Such an embodiment is particularly expedient in order to effectively counter possible stability problems which could arise in the case of long-term storage of ready-made bone replacement materials according to the invention.
- the bone substitute materials according to the invention are used in the form of such an implantation set in such a way that shortly before or during the surgical intervention for the implantation the porous matrix of the respective implant material is loaded with the FGF-containing solution in the manner described above.
- Such an embodiment is particularly expedient in the event that the porous matrix is itself formed by a shaped implant body, the material being primarily mineral, preferably ceramic, and in particular sintered bone ceramic.
- the bone substitute material according to the invention thus represents an at least equivalent substitute for autologous and homologous bone grafts or is a significant improvement in terms of healing behavior for other forms of bone substitute.
- Spongiosa-hydroxyapatite bone ceramic blanks manufactured according to DE 40 28 683, are used to produce cylindrical shaped bodies of 10.00 mm in height and 9.55 mm in diameter using a diamond milling machine.
- Some of these shaped bodies are each impregnated with 100 ⁇ l of a solution containing 50 ⁇ g of recombinantly produced human bFGF, dried and stored at 4-6 ° C. until the time of implantation.
- the other molded articles are used for comparison purposes.
- New bone formation in the contact area of the bone bed and implant; amorphous DBM is still available.
- New bone formation from the bone bed covering about 1/3 to 1/2 of the implant; partial incorporation.
- Porous spongiosa-hydroxyapatite bone ceramic moldings (according to Example 1; unloaded) are placed in appropriately designed thermoformed packaging moldings, the chambers of which correspond exactly to the dimensions (only a small residual volume) of the moldings.
- the deep-drawn parts are sealed, sterilized and surrounded with an outer packaging.
- bFGF solution is freeze-dried in citrate buffer (10 mmol; pH 5.0) and after addition of sucrose solution (9%) and filled into ampoules. Ampoule filling and ampoule volume are coordinated so that the subsequent loading of the ceramic molded body corresponds to 50 ⁇ g bFGF / cm3 block volume.
- Molded implant packs and bFGF ampoules form packing units as implantation sets.
- the bFGF solution is reconstituted in citrate buffer (pH 5.0) and then drawn onto a sterile syringe.
- the bFGF solution is injected through the sterile inner packaging into the thermoformed container of the ceramic molded body.
- the injection volume is dimensioned so that the molded body is completely immersed in the bFGF solution. Excess bFGF solution is sucked back into the syringe after approx. 1 minute.
- the ceramic molded body holds about as much solution as its pore volume.
- the loaded molded article can be implanted after opening the primary packaging.
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Abstract
Description
Die Erfindung betrifft Knochenersatzmaterialien, die in einer porösen Matrix ein oder mehrere Polypeptide mit der biologischen Wirkung von Fibroblasten-Wachstumsfaktoren enthalten.The invention relates to bone substitute materials which contain one or more polypeptides with the biological effect of fibroblast growth factors in a porous matrix.
Unter Knochenersatzmaterialien sind Materialien zu verstehen, die als Implantate für den Ersatz oder die Rekonstitution von Knochenstrukturen aufgrund von Defekten nach krankheits- oder unfallbedingten operativen Eingriff dienen. Beispielhaft zu nennen sind Implantatformkörper wie Knochenprothesen verschiedenster Art, Knochenverbindungselemente etwa in Form von Markraumnägeln, Knochenschrauben und Osteosyntheseplatten, Implantatmaterialien zur Auffüllung von Spongiosa-Knochendefekten oder von Zahnextraktionshöhlen sowie zur plastischchirurgischen Behandlung von Konturdefekten im Kiefer-Gesichtsbereich.Bone replacement materials are understood to mean materials that serve as implants for the replacement or reconstitution of bone structures due to defects after a surgical or illness-related surgical intervention. Examples include implant shaped bodies such as various types of bone prostheses, bone connecting elements, for example in the form of medullary cavity nails, bone screws and osteosynthesis plates, implant materials for filling cancellous bone defects or tooth extraction cavities, and for plastic-surgical treatment of contour defects in the jaw facial area.
Für den Einheilungsprozeß werden solche Implantatmaterialien als besonders günstig angesehen, die eine hohe Bioaktivität aufweisen, nämlich dahingehend, daß sie im Organismus angenommen und in ihm integriert werden. Im Falle von Knochenersatzmaterial bedeutet dies, daß es bald mit körpereigenem Gewebe, inbesondere mit dem Knochen, fest und dauerhaft verwachsen soll.For the healing process, such implant materials are regarded as particularly favorable if they have a high bioactivity, namely in that they are accepted in the organism and be integrated into it. In the case of bone substitute material, this means that it should soon grow firmly and permanently with the body's own tissue, in particular with the bone.
Es ist bekannt, daß bislang die günstigsten Einheilungsresultate praktisch nur mit körpereigenen Materialien, d.h. also mit Knochentransplantaten, erreicht werden. Die Verfügbarkeit von Knochentransplantaten ist naturgemäß begrenzt. Autologe Transplantate, also Transplantate vom selben Individuum sind, sofern überhaupt in geeigneter Form und Menge vorhanden, nur durch mindestens einen zusätzlichen operativen Eingriff entnehmbar, wodurch wiederum ein zusätzlicher Heilungsvorgang am Entnahmeort bedingt wird. Gleiches gilt prinzipiell auch für homologe Transplantate, also Transplantate von Spenderindividuen der gleichen Art. Bei diesen kommen noch Probleme der Verträglichkeit hinzu sowie auch die heute immer noch nicht völlig auszuschließende Infektionsgefahr mit Viren, wie insbesondere Hepatitis- und HIV-Viren. Weiterhin ist die Lagerung von Spendermaterial in Knochenbanken aufwendig und letztendlich zeitlich nur begrenzt.It is known that so far the cheapest healing results have been made practically only with the body's own materials, i.e. with bone grafts. The availability of bone grafts is naturally limited. Autologous grafts, that is, grafts from the same individual, if available in a suitable form and quantity, can only be removed by at least one additional surgical procedure, which in turn requires an additional healing process at the removal site. In principle, the same also applies to homologous transplants, that is to say transplants from donor individuals of the same type. In addition, there are problems of tolerance as well as the risk of infection with viruses, such as, in particular, hepatitis and HIV viruses, which can still not be completely ruled out today. Furthermore, the storage of donor material in bone banks is complex and ultimately only limited in time.
Implantatmaterialien für den Knochenersatz aus nicht körperverwandten synthetischen oder aus körperverwandten Materialien können, je nach Natur und Beschaffenheit, ein bioinertes bis bioaktives Verhalten zeigen. Die Einheilungsresultate von körpereigenen Knochentransplantaten konnten bislang jedoch noch von keinem synthetischen Implantatmaterial erreicht werden.Bone replacement implant materials made of synthetic or non-body related materials can, depending on their nature and nature, show bioinert to bioactive behavior. However, the healing results of the body's own bone grafts have not yet been achieved by any synthetic implant material.
Der Erfindung lag daher die Problemstellung zugrunde, ein Knochenersatzmaterial zur Verfügung zu stellen, dessen biologische Aktivität der von körpereigenen Knochentransplantaten möglichst nahe kommt.The invention was therefore based on the problem of providing a bone replacement material whose biological activity comes as close as possible to that of the body's own bone grafts.
Es wurde nun gefunden, daß dies von einem Knochenersatzmaterial erreicht wird, das in einer porösen Matrix ein oder mehrere Polypeptide mit der biologischen Wirkung von Fibroblasten-Wachstumsfaktoren enthält.It has now been found that this is achieved by a bone substitute material which contains one or more polypeptides in a porous matrix with the biological effect of fibroblast growth factors.
Gegenstand der Erfindung ist daher ein Knochenersatzmaterial, das in einer porösen Matrix ein oder mehrere Polypeptide mit der biologischen Wirkung von Fibroblasten-Wachstumsfaktoren enthält.The invention therefore relates to a bone substitute material which contains one or more polypeptides with the biological effect of fibroblast growth factors in a porous matrix.
Gegenstand der Erfindung ist insbesondere ein derartiges Knochenersatzmaterial, in dem die poröse Matrix eine mineralische Matrix, vorzugsweise auf Basis von Calcium-Mineralien darstellt.The invention particularly relates to such a bone substitute material in which the porous matrix is a mineral matrix, preferably based on calcium minerals.
Fibroblasten-Wachstumsfaktoren (Fibroblast Growth Factors, FGF), die zur Klasse der körpereigenen Peptid-Wachstumsfaktoren gehören, wurden usprünglich als Substanzen in Gehirn und Hypophyse nachgewiesen und daraus isoliert und zeigten eine das Wachstum von Fibroblasten fördernde Aktivität. FGFs sind bekannt als wirksame gefäßbildende Faktoren, die u.a. für die Neovaskularisation bei der Wundheilung verantwortlich sind. Nähere Details zu FGFs einschließlich ihrer Abwandlungsprodukte, zu ihrer Isolierung bzw. Herstellung, ihrer Struktur, ihrer biologischen Aktivitäten und deren Mechanismen sowie zu entsprechenden medizinischen Anwendungen können der inzwischen umfangreichen Fachliteratur entnommen werden. Eine umfassende Übersicht bietet beispielsweise A. Baird and P. Böhlen, Fibroblast Growth Factors, in: Peptide Growth Factors and their Receptors I (editors: M.B. Sporn and A.B. Roberts) Springer Verlag Berlin, Heidelberg, New York 1990.Fibroblast growth factors (FGF), which belong to the class of the body's own peptide growth factors, were originally detected as substances in the brain and pituitary gland and isolated therefrom and showed a growth-promoting activity of fibroblasts. FGFs are known to be effective vascularizing factors that are responsible for, among other things, neovascularization in wound healing. Further details on FGFs including their modification products, their isolation or manufacture, their structure, Their biological activities and their mechanisms as well as corresponding medical applications can be found in the now extensive specialist literature. A comprehensive overview is provided, for example, by A. Baird and P. Böhlen, Fibroblast Growth Factors, in: Peptide Growth Factors and their Receptors I (editors: MB Sporn and AB Roberts) Springer Verlag Berlin, Heidelberg, New York 1990.
Neben einer Fülle von positiven Wirkungen von FGFs in verschiedensten Indikationsfeldern wurde in neuester Zeit auch in einzelnen Fällen über Einflüsse von FGFs bei der Knochenbildung berichtet, z.B. in Biomaterials 11, 38-40 (1990). In Acta Orthop. Scand. 60, (4) 473-476 (1989) wurde berichtet, daß in Implantaten aus demineralisierter Knochenmatrix (DBM), die mit rekombinantem humanen basischen FGF beladen waren und die Ratten intramuskulär implantiert wurden, ein erhöhter Anteil von mineralisiertem Gewebe gefunden wurde. DBM an sich ist bekannt als Knochenwachstums-fördernde Substanz, da in ihr selbst noch intakte körpereigene Faktoren verschiedenster Art mit Knochenwachstums-fördernder Aktivität enthalten sind. Die biologische Aktivität von DBM ist jedoch, je nach Herkunft und Vorbehandlung, unterschiedlich und in keiner Weise auf ein reproduzierbares Niveau standardisierbar. Darüber hinaus ist DBM als Implantatmaterial für den Knochenersatz aufgrund mangelnder mechanischer Festigkeit praktisch ungeeignet. Aus den publizierten Befunden war in keiner Weise abzuleiten, daß mit dem erfindungsgemäßen Knochenersatzmaterial ein Material zur Verfügung gestellt werden könnte, daß die mechanischen Eigenschaften künstlicher Implantatmaterialien mit der biologischen Aktivität vereint, wie sie nur Knochentransplantate aufweisen.In addition to an abundance of positive effects of FGFs in a wide variety of indication fields, influences of FGFs in bone formation have recently been reported in individual cases, for example in Biomaterials 11 , 38-40 (1990). In Acta Orthop. Scand. 60 , (4) 473-476 (1989) reported that an increased proportion of mineralized tissue was found in demineralized bone matrix (DBM) implants loaded with recombinant human basic FGF and the rats implanted intramuscularly. DBM per se is known as a bone growth-promoting substance, since it contains intact in-body factors of various kinds with bone-growth-promoting activity. The biological activity of DBM is, depending on the origin and pretreatment, different and in no way standardized to a reproducible level. In addition, DBM is practically unsuitable as an implant material for bone replacement due to the lack of mechanical strength. From the published findings it was in no way deduced that with the bone replacement material according to the invention a material could be provided that combines the mechanical properties of artificial implant materials with the biological activity that only bone grafts have.
Die erfindungsgemäßen Knochenersatzmaterialien sind durch das gemeinsame Merkmal gekennzeichnet, daß sie in einer porösen Matrix ein oder mehrere Polypeptide mit der biologischen Wirkung von FGF enthalten. Als erfindungsgemäß geeignete Wachstumsfaktoren sind somit nicht nur die "klassischen" FGFs wie der saure Fibroblasten-Wachstumsfaktor (acidic Fibroblast Growth Factor, aFGF) und der basische Fibroblasten-Wachstumsfaktor (basic Fibroblast Growth Factor, bFGF) anzusehen, sondern alle peptidischen Wachstumfaktoren, die die biologische Wirkung von FGF zeigen.The bone substitute materials according to the invention are characterized by the common feature that they contain one or more polypeptides with the biological effect of FGF in a porous matrix. Suitable growth factors according to the invention are therefore not only the "classic" FGFs such as the acidic fibroblast growth factor (aFGF) and the basic fibroblast growth factor (basic Fibroblast Growth Factor, bFGF), but also all peptide growth factors which show biological effects of FGF.
Zum engeren Kreis von FGFs zählen native FGFs, insbesondere bovinen und humanen Ursprungs sowie rekombinant hergestellte FGFs. Bevorzugt sind insbesondere rekombinant hergestelltes humanes aFGF und bFGF. Näheres zu rekombinant hergestellten bovinen wie humanen aFGFs und bFGFs kann beispielsweise den folgenden Patentdokumenten entnommen werden: EP 228 449, EP 248 819, EP 259 953, EP 275 204. Zum weiteren Kreis von FGFs zählen auch Muteine, die sich von aFGF bzw. bFGF in einem gewissen Umfang in Zahl und/oder Sequenz der Aminosäuren unterscheiden ohne daß hiermit eine wesentliche Wirkungsveränderung verbunden ist. Der weitere Kreis von FGFs umfaßt schließlich noch verwandte Peptide mit zum Teil deutlich verschiedenen Aminosäuresequenzen mit der Wirkung von FGF sowie mit die Wirkung von FGF verstärkender Aktivität. Als Literaturhinweis seien beispielhaft die folgenden Patentdokumente angeführt: EP 148 922, EP 226 181, EP 281 822, EP 288 307, EP 319 052, EP 326 907 und WO 89-12645.The narrow circle of FGFs includes native FGFs, in particular bovine and human origin, and recombinantly produced FGFs. Recombinant human aFGF and bFGF are particularly preferred. More information on recombinantly produced bovines such as human aFGFs and bFGFs can be found, for example, in the following patent documents: EP 228 449, EP 248 819, EP 259 953, EP 275 204. Muteins which are different from aFGF or bFGF also include a further group of FGFs differ to a certain extent in the number and / or sequence of the amino acids without this being associated with a significant change in activity. The further circle of FGFs finally also includes related peptides with, in some cases, clearly different amino acid sequences with the effect of FGF as well as activity that enhances the effect of FGF. The following patent documents may be cited as references: EP 148 922, EP 226 181, EP 281 822, EP 288 307, EP 319 052, EP 326 907 and WO 89-12645.
Zu FGFs im Sinne der Erfindung zählen weiterhin Derivate dieser Peptide, die mit stabilisierenden und/oder aktivitätssteigernden Agentien erhalten werden. Es sind dies insbesondere gegen Säure stabilisierte Formen von aFGF und bFGF, die als stäbilisierende Agentien beispielsweise Glykosaminglykane wie Heparin, Heparinfragmente, Heparansulfat und Dermatansulfat oder Glukansulfate wie Dextransulfat und Cyclodextrinsulfat enthalten. FGF-Derivate dieser Art sind beispielsweise beschrieben in EP 251 806, EP 267 015, EP 312 208, EP 345 660, EP 406 856, EP 408 146, WO 89-12464, WO 90-01941 und WO 90-03797.FGFs in the sense of the invention also include derivatives of these peptides, which are obtained with stabilizing and / or activity-increasing agents. These are, in particular, acid-stabilized forms of aFGF and bFGF which contain, for example, glycosaminoglycans such as heparin, heparin fragments, heparan sulfate and dermatan sulfate or glucan sulfates such as dextran sulfate and cyclodextrin sulfate as stabilizing agents. FGF derivatives of this type are described, for example, in EP 251 806, EP 267 015, EP 312 208, EP 345 660, EP 406 856, EP 408 146, WO 89-12464, WO 90-01941 and WO 90-03797.
Besonders bevorzugt für die Anwendung in den erfindungsgemäßen Knochenersatzmaterialien sind Formen von rekombinant hergestelltem humanen bFGF wie sie in EP 248819 beschrieben sind.Forms of recombinantly produced human bFGF as described in EP 248819 are particularly preferred for use in the bone replacement materials according to the invention.
In den erfindungsgemäßen Knochenersatzmaterialien können die FGFs in einer Konzentration von 1 ng/cm³ - 1 mg/cm³ vorliegen. Die Wahl der Konzentration innerhalb des genannten Bereichs kann abhängig sein von Art und Form und der Aktivität des im Einzelfall einzusetzenden FGF sowie von der Natur des im Einzelfall vorgesehenen Implantatwerkstoffes und dessen ggf. inhärent vorhandene Bioaktivität. Vorzugsweise liegt die Konzentration an FGF im Bereich zwischen 1 µg/cm³ bis 100µg/cm³.In the bone replacement materials according to the invention, the FGFs can be present in a concentration of 1 ng / cm³ - 1 mg / cm³. The choice of concentration within the range mentioned may depend on the type and shape and the activity of the FGF to be used in the individual case, and on the nature of the implant material provided in the individual case and its inherent bioactivity. The concentration of FGF is preferably in the range between 1 µg / cm³ to 100µg / cm³.
In den erfindungsgemäßen Knochenersatzmaterialien können grundsätzlich alle bekannten und üblichen Implantatwerkstoffe vorliegen, sofern diese eine poröse Matrix zur Aufnahme von FGF darstellen oder aufweisen. Implantatwerkstoffe können in die Klassen mineralische, insbesondere keramische Werkstoffe, physiologisch akzeptable metallische Werkstoffe, physiologisch akzeptable Polymerwerkstoffe und Verbundwerkstoffe aus zwei oder mehr Materialien der genannten Art eingeteilt werden. Diese Werkstoffe können als Ganzes eine poröse Matrix bilden, etwa in Form von porösen Implantantformkörpern oder es können nur bestimmte Anteile des Werkstoffs als poröses Material vorliegen bzw. bestimmte Bereiche eines Implantatformkörpers eine poröse Matrix darstellen. Die letzten beiden Fälle können beispielsweise in der Form realisiert sein, daß ein Verbundwerkstoff oder ein Knochenzement eine poröse Komponente enthält bzw. ein Implantat mit einer porösen Oberflächenbeschichtung oder einer entsprechend aufgerauhten Oberfläche versehen ist.In principle, all known and customary implant materials can be present in the bone replacement materials according to the invention, provided that these represent or have a porous matrix for taking up FGF. Implant materials can be divided into the classes mineral, in particular ceramic materials, physiologically acceptable metallic materials, physiologically acceptable polymer materials and composite materials made of two or more materials of the type mentioned. These materials as a whole can form a porous matrix, for example in the form of porous implant shaped bodies, or only certain portions of the material can be present as porous material or certain areas of an implant shaped body can represent a porous matrix. The last two cases can be implemented, for example, in such a way that a composite material or a bone cement contains a porous component or an implant is provided with a porous surface coating or a correspondingly roughened surface.
Für die erfindungsgemäßen Knochenersatzmaterialien sind von der Werkstoffseite Materialien bevorzugt, die mineralischer und insbesondere keramischer Natur sind. Ein vorteilhafter Aspekt der Erfindung ist, daß an sich bioinerte Materialien, wie etwa oxidkeramische Werkstoffe, durch die Beladung mit FGF biologisch aktiviert werden können und so ein signifikant besseres Einwachs- und Einheilungsverhalten zeigen.For the bone replacement materials according to the invention, materials that are mineral and in particular ceramic in nature are preferred from the material side. An advantageous aspect of the invention is that bio-inert materials, such as oxide ceramic materials, can be biologically activated by loading with FGF and thus show significantly better waxing and healing behavior.
Bevorzugte mineralische Werkstoffe sind allerdings solche, die an sich bioaktiv sind. Dies trifft vornehmlich auf Materialien zu, die auf Calcium-haltigen Materialien basieren, wie inbesondere Calciumcarbonat, Calciumphosphate und von diesen Verbindungen abgeleitete Systeme. Aus der Gruppe der Calciumphosphate sind als bevorzugt Hydroxylapatit, Tricalciumphosphat und Tetracalciumphosphat zu nennen.However, preferred mineral materials are those that are bioactive per se. This applies primarily to materials based on calcium-containing materials, such as calcium carbonate, calcium phosphates and von systems derived from these connections. From the group of calcium phosphates, preferred are hydroxyapatite, tricalcium phosphate and tetracalcium phosphate.
Implantatwerkstoffe auf mineralischer Basis gewährleisten jedoch meist nur dann eine hohe mechanische Stabilität, wenn sie als Keramiken, d.h. also in Form von bei ausreichend hohen Temperaturen gesinterten Materialien bzw. Werkstücken eingesetzt werden.However, mineral-based implant materials usually only guarantee high mechanical stability if they are used as ceramics, i.e. thus in the form of materials or workpieces sintered at sufficiently high temperatures.
Knochenersatzmaterial auf Basis von Calciumphosphat-Keramiken gelten aufgrund ihrer chemischen Verwandtschaft mit der Mineralphase natürlicher Knochen als bioaktiv. Natürlicher Knochen besteht in seiner Mineralphase überwiegend aus Hydroxylapatit, einem Calciumphosphat der Summenformel Ca₅(PO₄)₃OH.Bone replacement material based on calcium phosphate ceramics is considered bioactive due to its chemical relationship with the mineral phase of natural bones. In its mineral phase, natural bone consists predominantly of hydroxyapatite, a calcium phosphate of the empirical formula Ca₅ (PO₄) ₃OH.
Hydroxylapatit synthetischen oder organischen Ursprungs, etwa aus natürlichem Knochenmaterial, ist daher ein häufig verwendeter Rohstoff zur Herstellung von Implantaten für den Knochenersatz. Hydroxylapatit-Keramik ist im Organismus im wesentlichen nicht resorbierbar. Das heißt, das körperfremde Material bleibt über lange Zeit praktisch unverändert erhalten und die Integration in den Organismus erfolgt im wesentlichen durch Verwachsen mit vorhandenem und sich neu bildenden Knochen und Einwachsen im umgebenden Gewebe.Hydroxyapatite of synthetic or organic origin, for example from natural bone material, is therefore a frequently used raw material for the production of implants for bone replacement. Hydroxyapatite ceramic is essentially non-absorbable in the organism. This means that the foreign material remains practically unchanged over a long period of time and the integration into the organism takes place essentially through overgrowth with existing and newly formed bone and ingrowth in the surrounding tissue.
Tricalciumphosphat ist unter bestimmten Umständen im Organismus resorbierbar. Tetracalciumphosphat ist im wesentlichen nicht bioresorbierbar.Tricalcium phosphate is absorbable in the organism under certain circumstances. Tetracalcium phosphate is essentially non-bioabsorbable.
Ein besonders günstiges Einwachsverhalten zeigen poröse Calciumphosphat-Keramiken. Besonders bevorzugt sind hierbei Materialien basierend auf natürlichem Knochen, der durch verschiedene Behandlungen mineralisiert und in ein keramisches System überführt wird, wobei die Struktur des Knochens möglichst erhalten bleiben soll. Den Verfahren gemeinsam ist die Entfernung der organischen Knochenbestandteile und die anschließende Verfestigung zur Keramik durch Sinterung bei entsprechenden Temperaturen. Die Entfernung der organischen Anteile erfolgt durch chemische Lösungsvorgänge oder durch pyrolytische Verfahren.Porous calcium phosphate ceramics show particularly favorable ingrowth behavior. Materials based on natural bone, which are mineralized by various treatments and converted into a ceramic system, are particularly preferred, the structure of the bone being retained as far as possible. Common to the processes is the removal of the organic bone components and the subsequent solidification to the ceramic by sintering at appropriate temperatures. The organic components are removed by chemical solution processes or by pyrolytic processes.
Näheres zu Knochenkeramiken und besonders günstige Verfahren zu ihrer Herstellung kann beispielsweise den Patentdokumenten DE 37 27 606, DE 39 03 695, DE 41 00 897 und DE 40 28 683 entnommen werden.More information on bone ceramics and particularly favorable methods for their production can be found, for example, in patent documents DE 37 27 606, DE 39 03 695, DE 41 00 897 and DE 40 28 683.
Knochenkeramikimplantate zeigen aufgrund ihrer ausgezeichneten Übereinstimmung mit dem Porensystem natürlichen Knochens erhebliche biologische Vorteile beim Einwachsverhalten und der Heilung im Organismus. Besonders bevorzugt ist SpongiosaKnochenkeramik aufgrund seiner hochporösen, dreidimensional offenporigen Netzwerkstruktur.Bone ceramic implants show considerable biological advantages in waxing behavior and healing in the organism due to their excellent agreement with the pore system of natural bone. Cancellous bone ceramic is particularly preferred due to its highly porous, three-dimensional open-pored network structure.
Formkörper aus keramischem Material, insbesondere der vorgenannten Art, werden in erster Linie für den Ersatz von tragenden Knochenstrukturen eingesetzt, die hohen mechanischen Belastungen Stand halten müssen. Beispiele hierfür sind Knochenprothesen und Knochenverbindungselemente wie etwa Markraumnägel, Knochenschrauben und Osteosyntheseplatten.Shaped bodies made of ceramic material, in particular of the type mentioned above, are primarily used for the replacement of load-bearing bone structures that have to withstand high mechanical loads. Examples of this are bone prostheses and bone connection elements such as intramedullary nails, bone screws and osteosynthesis plates.
Genauere klinische Untersuchungen haben gezeigt, daß offen vorliegende mineralische Kontaktflächen in Implantaten aus Calciumphosphat-Keramik bevorzugt die Neubildung von mineralischer Knochenmatrix stimulieren, wodurch sich eine feste Verwachsung des Implantats ergibt. Gefördert wird dies weiter noch bei porösen Implantaten, wo sich aufgrund der höheren Oberfläche und durch Einsprossung von neuem Knochengewebe eine besonders intensiv verzahnte und damit mechanisch stabile Verwachsung ausbildet. Bei Implantatmaterialien aus überwiegend polymeren Werkstoffen oder aus bioinerten Materialien bildet sich statt dessen zunächst bevorzugt im Kontaktbereich Bindegewebe, was zu einer nur mäßig festen Verwachsung führt.Closer clinical studies have shown that open mineral contact surfaces in implants made of calcium phosphate ceramic preferentially stimulate the formation of new mineral bone matrix, which results in a firm growth of the implant. This is further promoted in the case of porous implants, where, due to the higher surface area and the sprouting of new bone tissue, a particularly intensely interlocking and thus mechanically stable adhesion forms. In the case of implant materials made from predominantly polymeric materials or from bio-inert materials, connective tissue initially preferably forms in the contact area instead, which leads to only moderately firm adhesion.
Es hat sich nun gezeigt, daß die erfindungsgemäßen Knochenersatzmaterialien, im wesentlichen unabhängig von der Art des Werkstoffes, durch die Beladung mit FGF nach der Implantation im Kontaktbereich und, je nach dem ob sie aufgrund Porosität und/oder Resorption durchwachsbar sind, auch in ihrem Inneren eine erhebliche Neubildung von mineralischer Knochenmatrix stimulieren. Dies ist in jedem Fall signifikant höher als in entsprechenden unbeladenen Implantaten. Hierbei konnte bei mit FGF beladen porösen Implantaten auf Basis von Calcium-Mineralien, insbesondere Calciumphosphat-Keramiken, ein ausgeprägter synergistischer Effekt beobachtet werden. So zeigte sich in präklinischen Modellversuchen bei mit FGF beladenen Knochenkeramik-Implantaten sechs Wochen nach der Implantation eine vollständige Inkorporation in den Knochen durch Ein- und Durchwachsung mit neugebildeter, überwiegend mineralisierter Knochenmatrix. Ein vergleichbares Ergebnis wurde nur von autologen Knochentransplantaten erreicht, während beispielsweise bei unbeladener Knochenkeramik, DBM und mit DBM imprägnierter Knochenkeramik nur in den Kontaktbereichen zum vorliegenden Knochen eine Verwachsung durch Neubildung von Knochenmatrix festgestellt werden konnte. Es wird angenommen, daß sich die knochenwachstumsfördernde Wirkung von FGF und die Bioaktivität von Calcium-haltigen Implantatwerkstoffen, wie insbesondere Knochenkeramik, sich gegenseitig verstärken und so zu einer beschleunigten Einheilung und Inkorporation des Implantates führen.It has now been shown that the bone substitute materials according to the invention, essentially independent of the type of material, are loaded with FGF after the implantation in the contact area and, depending on whether they are permeable due to porosity and / or absorption, also inside stimulate a significant new formation of mineral bone matrix. In any case, this is significantly higher than in corresponding unloaded implants. Here, a pronounced synergistic effect could be observed with porous implants based on calcium minerals, in particular calcium phosphate ceramics, loaded with FGF. Preclinical model experiments with bone ceramic implants loaded with FGF showed complete incorporation into the bones six weeks after the implantation through ingrowth and infiltration with newly formed, predominantly mineralized bone matrix. A comparable result was only achieved with autologous bone grafts, while, for example, with unloaded bone ceramics, DBM and bone ceramics impregnated with DBM were only able to detect an adhesion caused by the formation of new bone matrix in the contact areas with the existing bone. It is believed that the bone growth-promoting effects of FGF and the bioactivity of calcium-containing implant materials, such as bone ceramic in particular, mutually reinforce one another and thus lead to accelerated healing and incorporation of the implant.
Der positive Einfluß von FGF auf das Einheilungsverhalten von Implantaten für den Knochenersatz ist, wie schon erwähnt, auf praktisch alle Arten von Knochenersatzmaterialien und Implantatwerkstoffen übertragbar, sofern diese so geartet bzw. gestaltet sind, daß sie eine poröse Matrix zur Aufnahme von FGF und Wiederabgabe an den Organismus aufweisen, zweckmäßigerweise zumindest vornehmlich im Kontaktbereich mit dem Körpergewebe. Diese Voraussetzungen erfüllen beispielsweise auch Implantate aus metallischen Werkstoffen, die in sich porös sind oder eine poröse Oberflächenbeschichtung, vorzugsweise aus dem bioaktiven Hydroxylapatit, oder die eine porös strukturierte oder zumindest aufgerauhte Oberfläche aufweisen. Gleiches gilt für Implantate aus polymeren Werkstoffen, anderen Keramikmaterialien oder aus Verbundwerkstoffen.As already mentioned, the positive influence of FGF on the healing behavior of implants for bone replacement can be transferred to practically all types of bone replacement materials and implant materials, provided that they are of such a design that they form a porous matrix for the absorption of FGF and re-release have the organism, expediently at least primarily in the area of contact with the body tissue. For example, implants made of metallic materials that are porous in themselves or have a porous surface coating, preferably made of bioactive hydroxyapatite, or that have a porous structured or at least roughened surface also meet these requirements. The same applies to implants made from polymeric materials, other ceramic materials or from composite materials.
Grundsätzlich können die erfindungsgemäßen Knochenersatzmaterialien nicht nur als Implantatformkörper vorliegen, sondern auch in Pulver- oder Granulatform, je nachdem wie es der Einsatzort und der Anwendungszweck erfordert.In principle, the bone replacement materials according to the invention can be present not only as shaped implants, but also in powder or granule form, depending on the location and the purpose of use.
Als Verbundmaterialien kommen vorzugsweise solche in Betracht, bei denen zumindest eine Komponente als poröse Matrix zur Aufnahme von FGF vorliegt. Zweckmäßig sind entsprechende Knochenersatzmaterialien auf Basis von Verbundwerkstoffen, in denen eine poröse mineralische Matrix in Pulver- oder Granulatform vorliegt und im Verbund mit einem physiologisch akzeptablen polymeren Werkstoff einen Formkörper bildet. Verbundmaterialien dieser Art können der einschlägigen Fachliteratur entnommen werden, beispielsweise den Patentdokumenten WO 90-01342 und WO 90-01955, in denen Implantatwerkstoffe auf Basis von Calciumphosphat- bzw. Knochenkeramikpartikeln und bioresorbierbarem Polymer beschrieben sind.Composite materials are preferably those in which at least one component is present as a porous matrix for receiving FGF. Appropriate bone replacement materials based on composite materials are expedient, in which a porous mineral matrix is in powder or granule form and forms a shaped body in combination with a physiologically acceptable polymer material. Composite materials of this type can be found in the relevant technical literature, for example in patent documents WO 90-01342 and WO 90-01955, in which implant materials based on calcium phosphate or bone ceramic particles and bioresorbable polymer are described.
In analoger Weise kann auch die Bioaktivität von Knochenzementen gesteigert werden. Knochenzemente bestehen überwiegend aus Acrylatsystemen, die mineralische Füllstoffe, meist auf Basis von Calciumverbindungen, enthalten. Erfindungsgemäß kann beispielsweise mit FGF beladenes poröses Hydroxylapatitpulver bzw. -granulat als Füllstoffkomponente in Knochenzement eingesetzt werden.The bioactivity of bone cements can be increased in an analogous manner. Bone cements mainly consist of acrylate systems that contain mineral fillers, mostly based on calcium compounds. According to the invention, for example, porous hydroxylapatite powder or granulate loaded with FGF can be used as filler component in bone cement.
Die Herstellung der erfindungsgemäßen Knochenersatzmaterialien durch Beladung der jeweiligen porösen Matrix mit Polypeptiden mit der Wirkung von FGF ist an sich problemlos. Zweckmäßigerweise geht man von einer geeigneten flüssigen oder halbflüssigen Präparation von FGF, beispielsweise in Form einer gepufferten wäßrigen Lösung, einer Suspension oder eines Gels, aus und läßt diese in der vorgesehenen Dosierungsmenge in die poröse Matrix des Knochenersatzmaterials vollständig einziehen. Damit, bzw. nach einer ggf. erforderlichen Trocknung, ist das Knochenersatzmaterial bereits einsetzbar oder nach den für derartige Materialien für die medizinische Anwendung erforderlichen Vorsichtsmaßnahmen, lagerbar. Auf diese Weise sind poröse Implantatformkörper, vorzugsweise aus Knochenkeramik, mit poröser Oberfläche versehene Implantate und poröse partikelförmige Komponenten für Verbundwerkstoffe und Knochenzemente mit FGF beladbar.The production of the bone replacement materials according to the invention by loading the respective porous matrix with polypeptides with the effect of FGF is per se problem-free. It is expedient to start from a suitable liquid or semi-liquid preparation of FGF, for example in the form of a buffered aqueous solution, a suspension or a gel, and allow it to be completely absorbed into the porous matrix of the bone substitute material in the intended dosage amount. With this, or after a possibly necessary Drying, the bone replacement material can already be used or can be stored according to the precautionary measures required for such materials for medical use. In this way, porous shaped implants, preferably made of bone ceramic, implants provided with a porous surface and porous particulate components for composite materials and bone cements can be loaded with FGF.
In einer bevorzugten Ausführungsform liegt das erfindungsgemäße Knochenersatzmaterial in Form eines gebrauchsfertigen Implantationssets aus zwei oder mehr getrennten Komponenten vor, worin eine Komponente die poröse Matrix und eine andere Komponente eine Lösung des Polypeptids mit der Wirkung von FGF beinhaltet. Eine derartige Ausführungsform ist besonders zweckmäßig, um mögliche Stabilitätsprobleme, die bei einer Langzeitlagerung von bereits fertig konfektionierten erfindungsgemäßen Knochenersatzmaterialien auftreten könnten, wirksam zu begegnen. So wurde beispielsweise in der Fachliteratur berichtet, daß Calciumionen, die ja in den hier bevorzugten Werkstoffen vorliegen, einen destabilisierenden Einfluß auf FGF ausüben können. Die Anwendung der erfindungsgemäßen Knochenersatzmaterialien in Form eines derartigen Implatationssets erfolgt in der Weise, daß man kurz, vor oder während des chirurgischen Eingriffs für die Implantation die poröse Matrix des jeweiligen Implantatwerkstoffes mit der FGF-enthaltenden Lösung in der vorbeschriebenen Weise belädt. Besonders zweckmäßig ist eine derartige Ausführungsform für den Fall, daß die poröse Matrix von einem Implantatformkörper selbst gebildet wird, wobei als Werkstoff in erster Linie mineralische, vorzugsweise keramische Werkstoffe und insbesondere gesinterte Knochenkeramik in Betracht kommen.In a preferred embodiment, the bone replacement material according to the invention is in the form of a ready-to-use implantation set consisting of two or more separate components, in which one component contains the porous matrix and another component contains a solution of the polypeptide with the effect of FGF. Such an embodiment is particularly expedient in order to effectively counter possible stability problems which could arise in the case of long-term storage of ready-made bone replacement materials according to the invention. For example, it was reported in the specialist literature that calcium ions, which are present in the preferred materials here, can have a destabilizing influence on FGF. The bone substitute materials according to the invention are used in the form of such an implantation set in such a way that shortly before or during the surgical intervention for the implantation the porous matrix of the respective implant material is loaded with the FGF-containing solution in the manner described above. Such an embodiment is particularly expedient in the event that the porous matrix is itself formed by a shaped implant body, the material being primarily mineral, preferably ceramic, and in particular sintered bone ceramic.
Je nach Ausführungsform stellt somit das erfindungsgemäße Knochenersatzmaterial einen zumindest gleichwertigen Ersatz für autologe und homologe Knochentransplantate dar oder ist für andere Formen des Knochenersatzes eine erhebliche Verbesserung in Bezug auf das Einheilungsverhalten.Depending on the embodiment, the bone substitute material according to the invention thus represents an at least equivalent substitute for autologous and homologous bone grafts or is a significant improvement in terms of healing behavior for other forms of bone substitute.
Aus Spongiosa-Hydroxylapatit-Knochenkeramikrohlingen, hergestellt nach DE 40 28 683, werden mittels Diamantfräse zylindrische Formkörper von 10,00 mm Höhe und 9,55 mm Durchmesser gefertigt.Spongiosa-hydroxyapatite bone ceramic blanks, manufactured according to DE 40 28 683, are used to produce cylindrical shaped bodies of 10.00 mm in height and 9.55 mm in diameter using a diamond milling machine.
Ein Teil dieser Formkörper wird jeweils mit 100 µl einer Lösung, enthalted 50 µg rekombinant hergestelltes humanes bFGF imprägniert, getrocknet und bei 4-6 °C bis zum Implantationszeitpunkt gelagert.Some of these shaped bodies are each impregnated with 100 μl of a solution containing 50 μg of recombinantly produced human bFGF, dried and stored at 4-6 ° C. until the time of implantation.
Die übrigen Formkörper dienen Vergleichszwecken.The other molded articles are used for comparison purposes.
- Tierart:Animal species:
- Minischwein, adult, weiblich, 6 Gruppen, 8 Implantate pro GruppeMini pig, adult, female, 6 groups, 8 implants per group
- Implantate:Implants:
-
- a) Spongiosa-Hydroxylapatit-Keramik mit FGF (gemäß Beispiel 1)a) Cancellous hydroxyapatite ceramic with FGF (according to Example 1)
- b) Spongiosa-Hydroxylapatit-Keramikb) Cancellous hydroxyapatite ceramic
- c) DBMc) DBM
- d) Spongiosa-Hydroxylapatit-Keramik, imprägniert mit DBMd) Cancellous hydroxyapatite ceramic, impregnated with DBM
- e) autologes Spongiosatransplantat, paßgenau mit Zwillingsfräse entnommen.e) Autologous cancellous bone graft, removed with a precise fit using a twin router.
- f) homologes Spongiosatransplantat, paßgenau mit Zwillingsfräse entnommen, Lagerung bis zum Implantationszeitpunkt bei -30 °Cf) Homologous cancellous bone graft, removed with a precise fit using a twin milling machine, stored at -30 ° C until the time of implantation
- Implantationsort:Implantation location:
- In das Patellagleitlager der Femurkondyle, linksseitig und rechtsseitigIn the patella slide bearing of the femoral condyle, left and right
Nach 6 Wochen werden die Knochen operativ entnommen und durch histologische Untersuchung die Knochenneubildung und die Mineralisation erfaßt.After 6 weeks, the bones are surgically removed and new bone formation and mineralization are determined by histological examination.
Knochenneubildung vom Knochenbett bis in das Zentrum des Implantats; vollständige InkorporationNew bone formation from the bone bed to the center of the implant; full incorporation
Marginaler knöcherner Kontakt mit dem Implantat; Einwachsen nur in den Randbereich des ImplantatsMarginal bone contact with the implant; Wax only in the edge area of the implant
Marginaler knöcherner Kontakt mit dem Implantat; Einwachsen nur in den Randbereich des ImplantatsMarginal bone contact with the implant; Wax only in the edge area of the implant
Knochenneubildung im Kontaktbereich von Knochenbett und Implantat; amorphes DBM liegt noch vor.New bone formation in the contact area of the bone bed and implant; amorphous DBM is still available.
Knochenneubildung vom Knochenbett bis in das Zentrum des Implantats; vollständige Inkorporation.New bone formation from the bone bed to the center of the implant; full incorporation.
Knochenneubildung vom Knochenbett, etwa 1/3 bis 1/2 des Implantats erfassend; teilweise Inkorporation.New bone formation from the bone bed, covering about 1/3 to 1/2 of the implant; partial incorporation.
Poröse Spongiosa-Hydroxylapatit-Knochenkeramikformkörper (nach Beispiel 1; unbeladen) werden in entsprechend gestaltete Tiefzieh-Verpackungsformteile gesetzt, deren Kammern exakt den Abmessungen (nur geringes Restvolumen) der Formkörper entsprechen. Die Tiefziehteile werden eingesiegelt sterilisiert und mit einer Umverpackung umgeben.Porous spongiosa-hydroxyapatite bone ceramic moldings (according to Example 1; unloaded) are placed in appropriately designed thermoformed packaging moldings, the chambers of which correspond exactly to the dimensions (only a small residual volume) of the moldings. The deep-drawn parts are sealed, sterilized and surrounded with an outer packaging.
bFGF-Lösung wird in Citrat-Puffer (10 mMol; pH 5,0) und nach Zugabe von Saccharose-Lösung ( 9 %) gefriergetrocknet und in Ampullen abgefüllt. Dabei werden Ampullenbefüllung und Ampullenvolumen so abgestimmt, daß die spätere Beladung der Keramikformkörper 50 µg bFGF/cm³ Blockvolumen entspricht.bFGF solution is freeze-dried in citrate buffer (10 mmol; pH 5.0) and after addition of sucrose solution (9%) and filled into ampoules. Ampoule filling and ampoule volume are coordinated so that the subsequent loading of the ceramic molded body corresponds to 50 µg bFGF / cm³ block volume.
Implantatformkörper-Packungen und bFGF-Ampullen bilden Packungseinheiten als Implantationssets.Molded implant packs and bFGF ampoules form packing units as implantation sets.
Die bFGF-Lösung wird in Citrat-Puffer (pH 5,0) rekonstituiert und anschließend auf eine sterile Spritze aufgezogen.The bFGF solution is reconstituted in citrate buffer (pH 5.0) and then drawn onto a sterile syringe.
Nach Öffnen der Umverpackung wird die bFGF-Lösung durch die sterile Innenverpackung in das Tiefziehbehältnis des Keramik-Formkörpers injiziert. Das Injektionsvolumen wird so bemessen, daß der Formkörper vollständig in die bFGF-Lösung eintaucht. Überschüssige bFGF-Lösung wird nach ca. 1 Minute in die Spritze zurückgesaugt. Der Keramik-Formkörper hält etwa so viel Lösung fest, wie seinem Porenvolumen entspricht.After opening the outer packaging, the bFGF solution is injected through the sterile inner packaging into the thermoformed container of the ceramic molded body. The injection volume is dimensioned so that the molded body is completely immersed in the bFGF solution. Excess bFGF solution is sucked back into the syringe after approx. 1 minute. The ceramic molded body holds about as much solution as its pore volume.
Der beladene Formkörper kann nach Öffnen der Primärverpackung implantiert werden.The loaded molded article can be implanted after opening the primary packaging.
Claims (25)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4121043A DE4121043A1 (en) | 1991-06-26 | 1991-06-26 | BONE REPLACEMENT MATERIAL WITH FGF |
| DE4121043 | 1991-06-26 |
Publications (3)
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|---|---|
| EP0520237A2 true EP0520237A2 (en) | 1992-12-30 |
| EP0520237A3 EP0520237A3 (en) | 1993-05-19 |
| EP0520237B1 EP0520237B1 (en) | 1999-01-27 |
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|---|---|---|---|
| EP92109712A Expired - Lifetime EP0520237B1 (en) | 1991-06-26 | 1992-06-10 | Bone replacement material containing fibroblast growth factors |
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| US (1) | US6118043A (en) |
| EP (1) | EP0520237B1 (en) |
| JP (2) | JPH07171211A (en) |
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| AT (1) | ATE176161T1 (en) |
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| CA (1) | CA2072244A1 (en) |
| CZ (1) | CZ281711B6 (en) |
| DE (2) | DE4121043A1 (en) |
| ES (1) | ES2128330T3 (en) |
| HU (1) | HUT65499A (en) |
| IE (1) | IE922067A1 (en) |
| MX (1) | MX9203253A (en) |
| NO (1) | NO922511L (en) |
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| RU (1) | RU2062622C1 (en) |
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| CN1058689C (en) * | 1998-02-05 | 2000-11-22 | 华东理工大学 | Porous calcium phosphate cement containing pore-creating agent |
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| DE10119096A1 (en) * | 2001-04-19 | 2002-10-24 | Keramed Medizintechnik Gmbh | New biologically functionalized coatings, useful for e.g. accelerating osteo-integration of implants, e.g. dental or joint implants, comprise resorbable calcium-phosphorus phase containing adhesion and/or signal proteins |
| EP2295088A1 (en) * | 2001-10-12 | 2011-03-16 | Osteotech, Inc., | Improved bone graft |
| US7959941B2 (en) | 2001-10-12 | 2011-06-14 | Warsaw Orthopedic, Inc. | Bone graft comprising a demineralized bone matrix and a stabilizing agent |
| EP1604649A1 (en) * | 2004-06-09 | 2005-12-14 | Scil Technology GmbH | Composite material for use as protein carrier |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ194692A3 (en) | 1993-01-13 |
| JPH07171211A (en) | 1995-07-11 |
| HUT65499A (en) | 1994-06-28 |
| EP0520237A3 (en) | 1993-05-19 |
| DE4121043A1 (en) | 1993-01-07 |
| CA2072244A1 (en) | 1992-12-27 |
| CZ281711B6 (en) | 1996-12-11 |
| AU1854692A (en) | 1993-01-07 |
| IE922067A1 (en) | 1992-12-30 |
| NO922511D0 (en) | 1992-06-25 |
| KR930000129A (en) | 1993-01-15 |
| MX9203253A (en) | 1994-03-31 |
| ES2128330T3 (en) | 1999-05-16 |
| TW293776B (en) | 1996-12-21 |
| RU2062622C1 (en) | 1996-06-27 |
| ZA924780B (en) | 1993-04-28 |
| ATE176161T1 (en) | 1999-02-15 |
| DE59209624D1 (en) | 1999-03-11 |
| NO922511L (en) | 1992-12-28 |
| PL172728B1 (en) | 1997-11-28 |
| AU652839B2 (en) | 1994-09-08 |
| HU9202123D0 (en) | 1992-10-28 |
| JP2003093495A (en) | 2003-04-02 |
| EP0520237B1 (en) | 1999-01-27 |
| US6118043A (en) | 2000-09-12 |
| PL295001A2 (en) | 1992-12-28 |
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